Process for preparing a 3-exomethylenecepham sulfoxide from penicillin sulfoxides

ABSTRACT

A penicillin sulfoxide ester is reacted with an N-chloro halogenating agent at a temperature of from about 75° C. to about 135° C. and in the presence of an alkylene oxide and calcium oxide to produce a 2-chlorosulfinylazetidin-4-one intermediate. The intermediate, upon separation from the alkylene oxide, calcium oxide, and any conversion products of both the alkylene oxide and calcium oxide, can be treated with stannic chloride to produce a 3-exomethylenecepham sulfoxide.

BACKGROUND OF THE INVENTION

In the recently issued United States Patent No. 3,843,682 there isdisclosed a process for preparing3-methyl-2-(2-chlorosulfinyl-4-oxo-3-imido-1-azetidinyl)-3-butenoateesters, variously termed "2-chlorosulfinyl-3-imido-azetidin-4-ones".These compounds are prepared from the corresponding penicillin sufloxideesters by reaction of the latter with sulfuryl chloride at a temperatureof from about 75° C. to about 120° C. The compounds which are preparedby this known process are exclusively the 3-imido substituted2-chlorosulfinylazetidin-4-ones since the process is limited to the useof the 6-imido penicillin sulfoxide esters as starting material. Thereis no disclosure of the use of or the possibility to use the 6-amidopenicillin sulfoxide esters, including the conveniently obtainablepenicillin sulfoxide derivatives of the naturally occurring Penicillin Gand/or Penicillin V. When one attempts to carry out the reactiondisclosed in U.S. Pat. No. 3,843,682 using a 6-amido penicillinsulfoxide ester as starting material, the product which is obtained is acomplex mixture containing no 2-chlorosulfinylazetidin-4-one product,or, at most, the latter in a quantity so minute as to be undetectable byordinary analytical techniques. Therefore, this previously disclosedmethod has significant deficiencies since it requires the absence of anamide hydrogen in the 6-position of the penicillin sulfoxide startingmaterial.

In co-pending Application Ser. No. 673,017 filed Apr. 2, 1976, a methodfor preparing sulfinyl chloride intermediates from 6-amido penicillinsulfoxide esters is provided. This method involves treating thepenicillin sulfoxide with an N-chloro halogenating agent at atemperature of from about 75° C. to about 135° C.

It now has become apparent that the degree of conversion of the 6-amidopenicillin sulfoxide to the sulfinyl chloride in accordance with thereaction described in application Ser. No. 673,017 diminishesconsiderably when the reaction scale is increased beyond typicalresearch laboratory quantities, for example, in those instances in which50 grams or more of the penicillin sulfoxide starting material areemployed.

This invention is directed to the discovery that, in a large scalereaction (about 100 millimoles or more), the extent of conversion of a6-amido penicillin sulfoxide to its corresponding sulfinyl chloride canbe substantially increased by carrying out the reaction under specifiedconditions.

The 2-chlorosulfinylazetidin-4-ones produced by the process of thisinvention can be ring closed to produce a 3-exomethylenecepham sulfoxideester. Cyclization of the 2-chlorosulfinylazetidin-4-ones to theircorresponding 3-exomethylenecepham sulfoxides is accomplished by aFriedel-Crafts catalyst induced intramolecular reaction involving thesulfinyl chloride and the olefinic moieties of the azetidin-4-onestarting material. This reaction generally is carried out using stannicchloride as Friedal-Crafts catalyst.

SUMMARY OF THE INVENTION

This invention is directed to an improved process for preparing sulfinylchlorides. It is an object therefore of this invention to provide in aprocess for preparing a sulfinyl chloride of the formula ##STR1## byreacting a penicillin sulfoxide of the formula ##STR2## with an N-chlorohalogenating agent at a temperature of from about 75° C. to about 135°C. in an inert solvent under anhydrous conditions and in the presence ofan epoxide compound of the formula ##STR3## in which R_(x) is hydrogenor methyl; and in which, in the above formulae, R₁ is a carboxylic acidprotecting group; and R is

(a) hydrogen, C₁ -C₃ alkyl, halomethyl, cyanomethyl, benzyloxy,4-nitrobenzyloxy, t-butyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy,3-(2-chlorophenyl)-5-methylisoxazol-4-yl;

(b) the group R' in which R' is phenyl or phenyl substituted with 1 or 2halogens, protected hydroxy, nitro, cyano, trifluoromethyl, C₁ -C₄alkyl, or C₁ -C₄ alkoxy;

(c) a group of the formula R"---(Q)_(m) --CH₂ -- in which R" is R' asdefined above, 1,4-cyclohexadienyl, 2-thienyl, or 3-thienyl; m is 0 or1; and Q is O or S; subject to the limitation that when m is 1, R" isR'; or

(d) a group of the formula ##STR4## in which R" is as defined above, andW is protected hydroxy or protected amino; the improvement whichcomprises carrying out the reaction in the presence of calcium oxide.

This invention also is directed to a process for preparing3-exomethylenecepham sulfoxides. It is a further object therefore ofthis invention to provide in a process for preparing a3-exomethylenecepham sulfoxide of the formula ##STR5## by

(1) reacting a penicillin sulfoxide of the formula ##STR6## with anN-chloro halogenating agent at a temperature of from about 75° C. toabout 135° C. in an inert solvent under anhydrous conditions and in thepresence of an epoxide compound of the formula ##STR7## in which R_(x)is hydrogen or methyl; and in which, in the above formulae, R₁ is acarboxylic acid protecting group; and R is

(a) hydrogen, C₁ -C₃ alkyl, halomethyl, cyanomethyl, benzyloxy,4-nitrobenzyloxy, t-butyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy,3-(2-chlorophenyl)-5-methylisoxazol-4-yl;

(b) the group R' in which R' is phenyl or phenyl substituted with 1 or 2halogens, protected hydroxy, nitro, cyano, trifluoromethyl, C₁ -C₄alkyl, or C₁ -C₄ alkoxy;

(c) a group of the formula R"--(Q)_(m) --CH₂ -- in which R" is R' asdefined above, 1,4-cyclohexadienyl, 2-thienyl, or 3-thienyl; m is 0 or1; and Q is O or S; subject to the limitation that when m is 1, R" isR'; or

(d) a group of the formula ##STR8## in which R" is as defined above, andW is protected hydroxy or protected amino; to produce a sulfinylchloride of the formula ##STR9## in which R and R₁ are as aforedefined;

(2) treating the resulting reaction mixture to remove said epoxidetherefrom;

(3) filtering insolubles from the epoxide-free mixture; and

(4) treating said epoxide-free mixture with a Friedel-Crafts catalyst ata temperature of from about -20° C. to about +100° C. to produce theaforementioned 3-exomethylenecepham sulfoxide; the improvement whichcomprises carrying out step (1) in the presence of calcium oxide.

DETAILED DESCRIPTION OF THE INVENTION

As delineated hereinabove, the process of this invention is directed tothe preparation of sulfinyl chlorides of the formula ##STR10##

R₁ in the above formula denotes a carboxylic acid protecting group, and,preferably, one which is removable by acid treatment or byhydrogenation. Preferred carboxylic acid protecting groups include, forexample, C₄ -C₆ tertalkyl, 2,2,2-trihaloethyl, 2-iodoethyl, benzyl,p-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl,benzhydryl, C₂ -C₆ alkanoyloxymethyl, dimethylallyl, phenacyl, orp-halophenacyl, in any of the above which halo denotes chlorine, bromineor iodine.

Specific illustrations of the preferred carboxylic acid protectinggroups of the sulfinyl chlorides produced by the process of thisinvention include, for example, t-butyl, t-amyl, t-hexyl,2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2-iodoethyl, benzyl,p-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl,benzhydryl, acetoxymethyl pivaloyloxymethyl, propionoxymethyl, phenacyl,p-chlorophenacyl, p-bromophenacyl, and the like.

Preferred carboxylic acid protecting groups are t-butyl, benzyl,p-nitrobenzyl, p-methoxybenzyl, benzhydryl, and 2,2,2-trichloroethyl.Highly preferred groups are p-nitrobenzyl and 2,2,2-trichloroethyl, and,most preferably, p-nitrobenzyl.

The amide function of the sulfinyl chlorides prepared by the process ofthis invention has the formula ##STR11## A preferred subclass of thisamide function comprises those moieties in which R is

(a) hydrogen, C₁ -C₃ alkyl, halomethyl, cyanomethyl, benzyloxy,4-nitrobenzyloxy, t-butyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy,3-(2-chlorophenyl)-5-methylisoxazol-4-yl;

(b) the group R' in which R' is phenyl or phenyl substituted with 1 or 2halogens, protected hydroxy, nitro, cyano, trifluoromethyl, C₁ -C₄alkyl, or C₁ -C₄ alkoxy; or

(c) a group of the formula R"--(Q)_(m) --CH₂ -- in which R" is R' asdefined above, 1,4-cyclohexadienyl, 2-thienyl, or 3-thienyl; m is 0 or1; and Q is O or S; subject to the limitation that when m is 1; R" isR'.

Specific illustrations of the group R include, for example, hydrogen,methyl, ethyl, n-propyl, isopropyl, chloromethyl, bromomethyl,cyanomethyl, benzyloxy, 4-nitro-benzyloxy, t-butyloxy,2,2,2-trichloroethoxy, 4-methoxy-benzyloxy, phenyl, 2-chlorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-formyloxyphenyl,4-nitrophenyl, 2-cyanophenyl, 4-trifluoromethylphenyl, 3-methylphenyl,2-ethylphenyl, 4-n-propylphenyl, 4-t-butylphenyl, 2-methoxy-phenyl,4-ethoxyphenyl, 3-isopropyloxyphenyl, 4isobutyloxy-phenyl,1,4-cyclohexadienylmethyl, benzyl, 3-bromobenzyl, 2,5-dichlorobenzyl,4-chloroacetoxybenzyl, 2-nitrobenzyl, 3-cyanobenzyl,4-trifluoromethylbenzyl, 3-methylbenzyl, 4-n-butylbenzyl,2-methoxybenzyl, 3-isopropoxybenzyl, phenoxymethyl, 3-iodophenoxymethyl,4-fluorophenoxymethyl, 3-benzyloxyphenoxymethyl,4benzhydryloxyphenoxymethyl, 3-trityloxyphenoxymethyl,4-nitrobenzyloxyphenoxymethyl, 4-trimethylsilyloxyphenoxymethyl,3-nitrophenoxymethyl, 4-cyanophenoxymethyl,2-trifluoromethylphenoxymethyl, 3-methylphenoxymethyl,4-n-propylphenoxymethyl, 4-n-butylphenoxymethyl, 3-methoxyphenoxymethyl,4-ethoxyphenoxy-methyl, phenylthiomethyl, 3-iodophenylthiomethyl,4-fluorophenylthiomethyl, 3-benzyloxyphenylthiomethyl,4-benzhydryloxyphenylthiomethyl, 3-trityloxyphenylthiomethyl,4-nitrobenzyloxyphenylthiomethyl, 4-trimethylsilyloxyphenylthiomethyl,3-nitrophenylthiomethyl, 4-cyanophenylthiomethyl,2-trifluoromethylphenylthiomethyl, 3-methylphenylthiomethyl,4-n-propylphenylthiomethyl, 4-n-butylphenylthiomethyl, 3-methoxyphenylthiomethyl, 4-ethoxyphenylthiomethyl,α-(benzhydryloxy)-thien-2-ylmethyl,α-(4-nitrobenzyloxy)-thien-2-ylmethyl,α-(t-butyloxycarbonylamino)-thien-2-ylmethyl,α-(formyloxy)-thien-3-ylmethyl, α-(benzyloxy)-thien-3-ylmethyl,α-(benzyloxycarbonylamino)-thien-3-ylmethyl,α-(chloroacetoxy)-thien-2-ylmethyl, α-(t-butyloxy)-thien-2-ylmethyl,α-(4-nitrobenzyloxycarbonylamino)-thien-2-ylmethyl, α-trityloxybenzyl,α-(4-methoxybenzyloxy)benzyl,α-(2,2,2-trichlorethoxycarbonylamino)benzyl,α-(trimethylsilyloxy)-4-bromobenzyl,α-(benzhydryloxycarbonylamino)-3-chlorobenzyl,α-(trimethylsilylamino)-4-fluorobenzyl, α,4-di(formyloxy)benzyl,α-(4-nitrobenzyloxycarbonylamino)-3-chloroacetoxybenzyl,α-(4-methoxybenzyloxycarbonylamino)-4-benzhydryloxybenzyl,α-benzyloxy-3-nitrobenzyl, α-(4-nitrobenzyloxy)-2-cyanobenzyl,α-(t-butoxycarbonylamino)-4-trifluoromethylbenzyl,α-formyloxy-4-methylbenzyl, α-benzyloxycarbonylamino-3-n-butylbenzyl,α-(benzyloxycarbonylamino)-4-methoxybenzyl,α-formyloxy-3-isopropoxybenzyl, thien-2-ylmethyl, thien-3-ylmethyl,3-(2-chlorophenyl)-5-methylisoxazol-4-yl, and the like.

Of the groups defined by the term R, those which are especiallypreferred are those of the formula R"--(Q)_(m) --CH₂ 13 . Of the latterclass, highly preferred groups are those in which R" is 2-thienyl orphenyl. When R" is phenyl, it is more preferred that, when m is 1, Q isoxygen.

In portions of the definition provided herein for the group R, the terms"protected amino", "protected hydroxy", and "protected carboxy" areemployed.

The term "protected amino", when employed herein, refers to an aminogroup substituted with one of the commonly employed amino blockinggroups such as t-butyloxycarbonyl, benzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 1-carbomethoxy-2-propenyl formed withmethyl acetoacetate, trimethylsilyl, and the like. Additional typicalamino protecting groups are described by J. W. Barton in ProtectiveGroups in Organic Chemistry, J. F. W. McOmie, Ed., Plenum Press, NewYork, N. Y., 1973, Chapter 2. Any of these are recognized as usefulwithin the meaning of the term "protected amino" employed herein.

The term "protected hydroxy", when employed herein, refers to thereadily cleavable groups formed with an hydroxyl group such as aformyloxy group, a chloroacetoxy group, a benzyloxy group, abenzhydryloxy group, a trityloxy group, a 4-nitrobenzyloxy group, atrimethylsilyloxy group, and the like. Other hydroxy protecting groups,isncluding those described by C. B. Reese in Protecting Groups inOrganic Chemistry, supra, Chapter 3, are considered to be within theterm "protected hydroxy" as used herein.

The terms "protected carboxy" and "carboxylic acid protecting group",when employed herein, refer to a carboxy group which has been protectedby one of the commonly used carboxylic acid protecting groups employedto block or protect the carboxylic acid functionality of a compoundwhile a reaction or sequence of reactions involving other functionalsites of the compound are carried out. Such protected carboxy groups arenoted for their ease of cleavage to the corresponding carboxylic acid byhydrolytic or by hydrogenolytic methods. Examples of carboxylic acidprotecting groups include t-butyl, benzyl, 4-methoxybenzyl, C₂ 14 C₆alkanoyloxymethyl, 2-iodoethyl, 4-nitrobenzyl, diphenylmethyl(benzhydryl), phenacyl, p-halophenacyl, dimethylallyl,2,2,2-trichloroethyl, succinimidomethyl and like ester forming moieties.The nature of such ester forming groups is not critical so long as theester formed therewith is stable under the reaction conditions of theprocess of this invention. Furthermore, other known carboxy protectinggroups such as those described by E. Haslam in Protective Groups inOrganic Chemistry, supra, Chapter 5, are considered to be within theterm "protected carboxy" as used herein.

Preferred groups within the term "protected carboxy" are tert-butyl,p-methoxybenzyl, p-nitrobenzyl, benzhydryl, and 2,2,2-trichloroethyl.

In the foregoing definitions, hydroxy, amino, and carboxy protectinggroups, of course, are not exhaustively described. The function of thesegroups is to protect reactive functional groups during preparation of adesired product. They then are removed without disruption of theremainder of the molecule. Many such protecting groups, are well knownin the art, and their use is equally applicable in the process of thisinvention.

As will be apparent to those of ordinary skill in the penicillin andcephalosporin arts, any of the penicillin sulfoxide starting materialsused in the process of this invention are readily preparable fromavailable penicillin sources such as naturally occuring Penicillin Gand/or Penicillin V.

6-Aminopenicillanic acid (6-APA) can be prepared from either of theabove naturally-occuring penicillins by cleavage of the 6-acyl functionemploying techniques well known in the art.

It is possible to prepare, by widely recognized techniques and from6-APA, any of the starting materials of the process of this invention.For example, 6APA can be converted to the desired ester byesterification of the 3-carboxyl function employing any of severaltypical esterification techniques.

Furthermore, the amino group 6APA can be acylated to produce any of thegroups defined herein by the term ##STR12## . This is achieved byreacting 6APA with an activated form of the acid of the intended acylgroup. Such activated forms include the corresponding acid halides,anhydrides, or activated esters, such as the pentachlorophenyl ester.

Moreover, the penicillin can be oxidized to the sulfoxide under any of awide variety of recognized conditions, including treatment of thepenicillin with m-chloroperbenzoic acid or sodium periodate.

These conversions, cleavage to 6APA, esterification, acylation, andoxidation, can be carried out in any sequence consistent with theintended structural modifications. In any event, all such conversionscan be accomplished employing techniques, conditions, and reagentsreadily available to and well recognized by one of ordinary skill in theart.

Preferred penicillin sulfixide esters for use in the process of thisinvention are those having the formula ##STR13## in which m is 0 or 1,and, preferably, is 1, and R₁ is a carboxylic acid protecting group,and, preferably, is p-nitrobenzyl.

Correspondingly, the preferred sulfinyl chlorides prepared from theabove esters and by the process of this invention are those of theformula ##STR14## in which m is 0 or 1, and, preferably, is 1, and R₁ isa carboxylic acid protecting group, and, preferably, is p-nitrobenzyl.

Other preferred penicillin sulfoxide esters for use in the process ofthis invention are those of the formula ##STR15## in which R₁ is acarboxylic acid protecting group, and, preferably, is p-nitrobenzyl.

Correspondingly, other preferred sulfinyl chlorides prepared from theabove esters and by the process of this invention are those of theformula ##STR16## in which R₁ is a carboxylic acid protecting group,and, preferably, is p-nitrobenzyl.

The sulfinyl chlorides produced by the process of this invention resultfrom the interaction of a penicillin sulfoxide ester with an N-chlorohalogenating agent at an elevated temperature.

By the term "N-chloro halogenating agent" is meant a reagent having atleast one chlorine bonded directly to a nitrogen atom with the remainingmoiety or moieties of the structure of the reagent havingelectron-withdrawing strength sufficient to produce, as by-product fromthe sulfinyl chloride preparation, a nitrogen-containing compound whichexhibits the following characteristics. The thus-producednitrogen-containing compound, first, will be one which corresponds tothe N-chloro halogenating agent but which has the chlorine atom replacedby a hydrogen atom. Secondly, the nitrogen-containing compound, dueprimarily to the properties of the electron-withdrawing moiety, will beinert to the sulfinyl chloride product.

The N-chloro halogenating agents which are employed in the process ofthis invention preferably are compounds of the formula ##STR17## inwhich R₄ is hydrogen, chloro, C₁ 14 C₃ alkyl, cyclohexyl, phenyl, orphenyl substituted with chloro, bromo, methyl, or nitro, and R₅ is R₆--X-- in which R₆ is C₁ -C₃ alkyl, cyclo hexyl, phenyl, or phenylsubstituted with chloro, bromo, methyl, or nitro, and X is or R₄ and R₅taken together with the nitrogen to which they are bonded define aheterocyclic structure of the formula in which Y is o-phenylene or--(CH₂)_(n) -- in which n is 2 or 3 ; or a structure of the formula inwhich Y is as hereinbefore defined.

Several types of preferred N-chloro compounds which can be employed inproducing the sulfinyl chlorides are described by the above definition.These N-chloro compounds include (a) ureas, (b) amides, (c) urethans,(d) sulfonamides, (e) sulfimides, and (f) imides.

The preferred N-chloro ureas which can be employed in this inventiongenerally have the formula ##STR18## in which R₄ is hydrogen, chloro, C₁-C₃ alkyl, cyclohexyl, pehnyl, or phenyl substituted with chloro, bromo,methyl, or nitro, and R₆ is C₁ -C₃ alkyl, cyclohexyl, phenyl, or phenylsubstituted with chloro, bromo, methyl, or nitro.

Illustrative of these ureas are

N,n'-dichloro-N-methylurea;

N,n'-dichloro-N-ethyl-N'-cyclohexylurea;

N,n'-dichloro-N-phenylurea;

N,n'-dichloro-N,N'-diphenylurea;

N,n'-dichloro-N-(p-tolyl)urea;

N,n'-dichloro-N-(m-chlorophenyl)-N'-methylurea;

N,n'-dichloro-N.N'-dicycloohexylurea;

N,n'-dichloro-N-isopropyl-N'-(p-tolyl)urea;

N,n'-didhloro-N-phenyl-N'-propylurea;

N,n'-dichloro-N-cyclohexyl-N'-(p-nitrophenyl)urea;

N,n,n'-trichloro-N-methylurea;

N,n,n'-trichloro-N-phenylurea; and the like.

The preferred N-chloro amides which can be employed in this inventiongenerally have the formula ##STR19## in which R₄ and R₆ are ashereinbefore defined.

Illustrative of these amides are N-chloroacetamide,N-chloropropionamide, N-chloro-N-methylacetamide, N,N-dichloroacetamide,N-chloro-N-cyclohexylacetamide, N-chloro-N-ethylbenzamide,N-chloro-p-chlorobenzamide, N-chloro-p-toluamide,N-chloro-N-phenylpropionamide, N-chloro-N-(m-bromophenyl)butyramide,N-chlorohexahydrobenzamide, N, 2,4-trichloroacetanilide, and the like.

The preferred N-chloro urethans which can be used in preparation of thesulfinyl chlorides in accordance with this invention generally have theformula ##STR20## in which R₄ and R₆ are as hereinbefore defined.

Illustrative of these urethans are methyl N,N-dichlorocarbamate, ethylN,N-dichlorocarbamate, phenyl N,N-dichlorocarbamate, cyclohexylN,N-dichlorocarbamate, methyl N-chlorocarbamate, ethylN-chlorocarbamate, ethyl N-cyclohexyl-N-chlorocarbamate, phenylN-chlororcarbamate, phenyl N-phenyl-N-chlorocarbamate, p-tolylN-chlorocarbamate, m-chlorophenyl N-methyl-N-chlorocarbamate, cyclohexylN-cyclohexyl-N-chlorocarbamate, isopropyl N-p-tolyl-N-chlorocarbamate,phenyl N-propyl-N-chlorocarbamate, cyclohexylN-p-nitrophenyl-N-chlorocarbamate, and the like.

The preferred N-chloro sulfonamides which can be used to prepare thesulfinyl chlorides in accordance with this invention have the formula##STR21## in which R₄ and R₆ are as hereinbefore defined.

Illustrative of the sulfonamides which can be employed as halogenatingagents are N,N-dichlorobenzene-sulfonamide,N,N-dichloromethanesulfonamide, N.N-dichloro-cyclohexanesulfonamide,N,N-dichlor-p-toluenesulfonamide, N-chloromethanesulfonamide,N-cyclohexyl-N-chlorobenzene-sulfonamide,N-cyclohexyl-N-chloroethanesulfonamide, N-chlorobenzenesulfonamide,N-phenyl-N-chlorobenzenesulfonamide, N-chloro-p-toluenesulfonamide,N-ethyl-N-chloro-m-nitrobenzenesulfonamide,N-methyl-N-chloro-m-choro-benzenesulfonamide,N-methyl-chloro-p-toluenesulfonamide,N-cyclohexyl-N-chlorocyclohexanesulfonamide,N-p-tolyl-N-chloroisopropanesulfonamide,N-propyl-N-chlorobenzene-sulfonamide,N-p-nitrophenyl-N-chlorocyclohexanesulfonamide, and the like.

A further preferred type of N-chloro halogenating agent which can beemployed in prepreparation of the sulfinyl chlorides is a sulfimide ofthe formula ##STR22## in which Y is o-phenylene, --CH₂ --CH₂ --, or--CH₂ --CH₂ --CH₂ --. These compounds include o-sulfobenzoicN-chloroimide, β-sulfopropionic N-chloroimide, and γ-sulfobutyricN-chloroimide.

Also preferred for use as N-chlorohalogenating agents in the preparationof the sulfinyl chlorides in accordance with this invention areN-chloroimides of the formula ##STR23## in which Y is o-phenylene, --CH₂--CH₂ --, or --CH₂ --CH₂ --CH.sub. 2 --. These compounds includeN-chlorophthalimide, N-chlorosuccinimide, and N-chloroglutarimide.

Many of the N-chloro halogenating agents employed in the process of thisinvention are available commercially, and any of them can be prepared bymethods well recognized throughout the chemical arts. Typical of theliterature sources which detail preparation of the N-chloro halogenatingagents are Bachand et al., J. Org., Chem. 39 (1974) pp. 3136-3138;Theilacker et al., Liebigs Ann. Chem. 703, (1967) pp. 34-36; andHouben-Weyl, Methoden der Organischen Chemie, Volume V/3, pp. 796-810.

N-chloro halogenating agents which are highly preferred for use in theprocess of this invention are N-chloro imides, particularlyN-chlorosuccinimide or N-chloro-phthalimide, and, more particularly,N-chlorophthalimide.

The reaction of the penicillin sulfoxide with the N-chloro halogenatingagent is carried out in the presence of an epoxide compound and calciumoxide. Generally, at least 1 mole and up to about 1.5 moles of thehalogenating agent are used for each mole of the penicillin sulfoxideester. An even larger excess of the halogenating agent can by employed;however, no advantage is gained thereby. Preferably, therefore, theratio of reactants is from about 1.0 to about 1.1 moles of halogenatingagent per mole of the penicillin sulfoxide ester. The resulting mixture,preferably dissolved in a suitable inert organic solvent, is heated to atemperature of from about 75° C. to about 135° C. Preferably, thetemperature of reaction is from about 100° C. to about 120° C., and,most preferably, is about 102° C. to about 110° C.

By "inert organic solvent" is meant an organic solvent which, under theconditions of sulfinyl chloride formation, does not appreciably reacteither with the reactants or with the products. Suitable inert organicsolvents are those having a boiling point at least as high as thetemperature of reaction and include, for example, aromatic hydrocarbonssuch as benzene, toluene, ehtylbenzene, cumene, and the like;halogenated hydrocarbons such as carbon tetrachloride, chlorobenzene,bromoform, bromobenzene, ethylene dichloride, 1,1,2-trichloroethane,ethylene dibromide, and the like; open chain hydrocarbons, such asheptane, octane, nonane, decane, and the like; any other appropriateinert solvents. Preferred solvents are those having a boiling pointwithin the range of the temperature at which the reaction is to becarried out, thereby permitting the reaction mixture to be refluxedwhile retaining temperature control. Particular conditions of reactioninclude the use of toluene or 1,1,2-trichloroethane as solvent with thetemperature of reaction being that developed under reflux conditions.

A requirement of the process of this invention is that the reaction becarried out under anhydrous conditions. It is not intended by the term"anhydrous conditions" to mean the total absence of any moisture;instead, this term means the avoidance in the reaction mixture of anysubstantial amount of moisture. This is accomplished by the exercise ofany of the recognized procedures for rendering a reaction systemanhydrous. The halogenating agent, since it generally will react withwater, normally will not be the source of moisture in the reactionmixture; typically, any excessive quantity of moisture in the reactionsystem arises from the presence of moisture in the solvent which isemployed. Generally, therefore, the solvent is pretreated to removeresidual amounts of water. The solvent can be rendered anhydrous to theextent herein contemplated by contacting it prior to use in the reactionwith a drying agent which will bind moisture and thereby effectivelyremove it from the solvent. Typical such drying agents include anhydroussodium sulfate, magnesium sulfate, sodium carbonate, potassiumcarbonate, calcium carbide, calcium chloride, calcium hydride, potassiumsulfate, calcium oxide, molecular sieves, particularly types 3A and 4 A,and the like.

In the event that the solvent is one with which water will azeotrope,moisture can be removed by subjecting the solvent to conditions ofreflux using known types of chemical equipment including the usualDean-Stark trap or the Barrett types of water traps which collect themoisture as it azeotropes out of the solvent medium.

The penicillin sulfoxide ester starting material itself may containmoisture. This can be removed by subjecting the penicillin sulfoxide toany of the typical drying techniques, including in vacuo drying in anoven at a low temperature upt to about 50° C. Additionally, thepenicillin sulfoxide ester can be added to the solvent and the mixturesubjected to azeotropic water removal.

The mixture containing the penicillin sulfoxide ester, the N-chlorohalogenating agent, the epoxide compound, and calcium oxide, generallyis heated at a temperature in the defined range for a period of fromabout 0.5 to about 4 hours, and preferably from about 1 to about 2hours, after which time the sulfinyl chloride can be isolated from thereaction mixture. Although the sulfinyl chloride can be isolated fromthe reaction mixture, it is not essential that it be isolated from thereaction mixture prior to being subjected to further reaction. Asindicated hereinabove, the sulfinyl chloride can be employed as anintermediate in the preparation of a 3-exomethylenecepham sulfoxide.When this is intended, although the sulfinyl chloride need not itself beisolated, the sulfinyl reaction mixture must first be treated in amanner to be further described hereinafter before it can be used inpreparation of the 3-exomethylenecepham sulfoxide.

As a portion of the disclosure provided in copending application Ser.No. 673,017 filed Apr. 2, 1976, it was indicated that in many instancesit is desirable to include a non-alkaline acid scavenger in the reactionmixture. This is recommended on the basis that, for some reason, not yetunderstood, small amounts of hydrogen chloride, detrimental to thereaction, can be liberated to the reaction system. A non-alkaline acidscavenger will remain entirely inert in the normal, hydrogenchloride-free reaction medium in which the sulfinyl chloride isgenerated; however, it will be come activated to the extent necessary toreact with any hydrogen chloride which may be formed and thereby toremove it from the reaction medium.

Typical disclosed non-alkaline acid scavengers include epoxide compoundssuch as ethylene oxide, propylene oxide, 1,2-epoxybutane,epichlorohydrin, 1,2-epoxy-3-phenoxy-proprane, and the like. Thesesubstances exhibit non-alkaline properties but, nevertheless, will reactwith and remove acidic substances from a reaction system.

It now has been discovered that, when the sulfinyl chloride preparationis carried out in the presence of a non-alkaline acid scavenger epoxidecompound, and particularly one selected from the group consisting ofpropylene oxide and 1,2-epoxybutane, the addition to the reactionmixture of calcium oxide is highly advantageous in promoting conversionof the penicillin sulfoxide to the desired sulfinyl chloride. This isespecially evident in those instances in which the scale of the reactioncontemplates about 50 g. or more of the penicillin sulfoxide startingmaterial. It has been discovered that the extent of conversion of thepenicillin sulfoxide to the sulfinyl chloride when carried out inaccordance with the process described in co-pending application Ser. No.673,017 filed Apr. 2, 1976, decreases significantly with increasingscale of reaction. The advantage of this invention therefore is directedin particular to those preparations of sulfinyl chloride in which atleast about 50 g. of penicillin sulfoxide starting material areemployed.

The amount of epoxide compound which is employed in the sulfinylchloride preparation need be an amount sufficient at least to accountfor any hydrogen chloride which may be formed. Although an excess of theepoxide compound therefore is not essential, an amount of about 2 toabout 10 moles, and particularly about 5 moles, of the epoxide compoundper mole of the penicillin sulfoxide customarily is employed. Such anexcess can be employed without adverse consequence in the preparation ofthe sulfinyl chloride. However, the presence of the excess epoxidecompound will become significant in those instances in which thereaction mixture containing the sulfinyl chloride product itself used inconversion to the corresponding 3-exomethylenecepham sulfoxide.Therefore, it is highly preferred that, prior to ring-closure using aFriedel-Crafts catalyst, any excess epoxide compound as well as anyproduct formed by reaction of the epoxide compound with hydrogenchloride be separated from the sulfinyl chloride reaction mixture. Thisgenerally can be accomplished by distillation of the reaction mixtureunder conditions and for a period sufficient to ensure removal of theexcess epoxide.

As noted, this invention contemplates the presence of a combination ofcalcium oxide and the epoxide compound during reaction of the penicillinsulfoxide with the N-chloro halogenation agent to form the sulfinylchloride. The amount of calcium oxide generally will range from about100 g. to about 500 g; and preferably from about 200 g. to about 250 g.,per mole of the penicillin sulfoxide starting material. The calciumoxide is present throughout the time of the sulfinyl chloridepreparation and during removal of excess epoxide compound. It is thenreadily removed by filtration from the residual reaction mixture.

A typical preparation of a sulfinyl chloride in accordance with theprocess of this invention is accomplished by mixing calcium oxide andmolar equivalents of the penicillin sulfoxide and the N-chlorohalogenating agent in a suitable pre-dried solvent. Propylene oxide or1,2-epoxybutane then is added, and the resulting mixture is heated tothe desired temperature of reaction for the intended period of reaction.Preferably, the solvent which is employed is one which, in conjunctionwith the amount of propylene oxide or 1,2-epoxybutane which is present,permits the temperature of reaction to be achieved and maintained byreflux of the reaction mixture. Toluene is a suitable such solvent. Uponcompletion of the reaction time, the reaction mixture is rapidlydistilled to remove excess epoxide. The remaining mixture is cooled andfiltered. Upon evaporation of the solvent, the sulfinyl chloride productis removed.

Examples of sulfinyl chlorides prepared by the process of the thisinvention include:

t-butyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate;

t-butyl3-methyl-2-(2-chlorosulfinyl-4-oxo-phenoxyacetamido-1-azetidinyl)-3-butenoate;

benzyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-formamido-1-azetidinyl)-3-butenoate;

2,2,2-trichloroethyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl)-3-butenoate;

p-nitrobenzyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-butyramido-1-azetidinyl)-3-butenoate;

p-methoxybenzyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-chloroacetamido-1-azetidinyl)-3-butenoate;

benzhydryl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-cyanoacetamido-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4-nitrobenzyloxycarbamido)-1-azetidinyl]-3-butenoate;

t-amyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-benzyloxycarbamido-1-azetidinyl)-3-butenoate;

t-hexyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(t-butyloxycarbamido)-1-azetidinyl]-3-butenoate;

2-iodoethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2,',2',2'-trichloroethoxycarbamido)-1-azetidinyl]-3-butenoate;

acetoxymethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-methoxybenzyloxycarbamido)-1-azetidinyl]-3-butenoate;

benzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-thienylacetamido)-1-azetidinyl]-3-butenoate;

t-amyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-benzamido-1-azetidinyl)-3-butenoate;

phenacyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-chlorobenzamido)-1-azetidinyl]-3-butenoate;

p-chlorophenacyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-formyloxybenzamido)-1-azetidinyl]-3-butenoate;

pivaloyloxymethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-nitrobenzamido)-1-azetidinyl]-3-butenoate;

isopropyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-cyanobenzamido)-1-azetidinyl]-3-butenoate;

succinimidomethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-trifluoromethylbenzamido)-1-azetidinyl]-3-butenoate;

phthalimidomethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-methylbenzamido)-1-azetidinyl]-3-butenoate;

t-butyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-methoxybenzamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(1',4'-cyclohexadienylacetamido)-1-azetidinyl]-3-butenoate;

2,2,2-trichloroethyl 3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-thienylacetamido)-1-azetidinyl]-3-butenoate;

p-methoxybenzyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl)-3-butenoate;

2,2,2-trichloroethyl3-methyl-2-(2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl)-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2',5'-dichlorophenylacetamido)-1-azetidinyl]-3-butenoate;

benzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-bromophenoxyacetamido)-1-azetidinyl]-3-butenoate;

t-butyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-chloroacetoxyphenylacetamido)-1-azetidinyl]-3-butenoate;

isobutyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-formyloxyphenoxyacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-nitrophenylacetamido)-1-azetidinyl]-3-butenoate;

p-methoxybenzy3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-nitrophenoxyacetamido)-1-azetidinyl]-3-butenoate;

benzhydryl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-cyanophenylacetamido)-1-azetidinyl]-3-butenoate;

p-bromophenacyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-cyanophenoxyacetamido)-1-azetidinyl]-3-butenoate;

propionoxymethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-trifluoromethylphenylacetamido)-1-acetidinyl]-3-butenoate;

2,2,2-tribromoethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-trifluoromethylphenoxyacetamido)-1-azetidinyl]-3-butenoate;

2-iodoethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-ethylphenylacetamido)-1-azetidinyl]-3-butenoate;

acetoxymethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-isopropylphenoxyacetamido)-1-azetidinyl]-3-butenoate;

t-butyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-ethoxyphenylacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-isopropoxyphenoxyacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(α-formyloxyphenylacetamido)-1-azetidinyl]-3-butenoate;

p-methoxybenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(α-benzhydryloxyphenylacetamido)-1-azetidinyl]-3-butenoate;

benzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2-thienyl-α-benzyloxyacetamido)-1-azetidinyl]-3-butenoate;

benzhydryl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(α-benzhydryloxyphenylacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(α-benzyloxycarbonylaminophenylacetamido)-1-azetidinyl]-3-butenoate;

t-butyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(α-t-butyloxycarbonylaminophenylacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-]2-chlorosulfinyl-4-oxo-3-(2-thienyl-α-p-nitrobenzyloxycarbonylaminoacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-thienylacetamido)-1-azetidinyl]-3-butenoate;

benzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-thienylacetamido)-1-azetidinyl]-3-butenoate;

p-methoxybenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-phenylthioacetamido-1-azetidinyl]-3-butenoate;

benzhydryl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2',5'-dichlorophenylthioacetamido)-1-azetidinyl]-3-butenoate;

t-butyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-chloroacetoxyphenylthioacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl 3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-nitrophenylthioacetamido)-1-azetidinyl]-3-butenoate;

p-nitrobenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(2'-cyanophenylthioacetamido)-1-azetidinyl]-3-butenoate;

p-methoxybenzyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-trifluoromethylphenylthioacetamido)-1-azetidinyl]-3-butenoate;

benzyl3-methyl-2-[[3-chlorosulfinyl-4-oxo-3-[3'-(2"-chlorophenyl)-5'-methylisoxazol-4'-ylcarbimido]-1-azetidinyl]]-3-butenoate;

acetoxymethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(3'-methylphenylthioacetamido)-1-azetidinyl]-3-butenoate;

2,2,2-trichloroethyl3-methyl-2-[2-chlorosulfinyl-4-oxo-3-(4'-methoxyphenylthioacetamido)-1-azetidinyl]-3-butenoate;and the like.

As hereinbefore noted, the sulfinyl chlorides produced by the process ofthis invention are useful as intermediates and can be ring-closed to thecorresponding 3-exomethylenecepham sulfoxides by subjection of thesulfinyl chloride to a Friedel-Crafts catalyst, such as, for example,stannic chloride.

The cyclization generally is carried out in the presence of a dry inertorganic solvent. Any of a wide variety of dry inert organic solvents maybe employed as the medium for the cyclization reaction. By "inertorganic solvent" is meant an organic solvent which, under the conditionsof cyclization, does not appreciably react either with the reactants orthe products. Since the sulfinyl chloride starting material, like otheracid chloride reagents, is susceptible to hydrolysis and to attack byother protic compounds, e.g. alcohols and amines, moisture and othersuch protic compounds should be excluded from the reaction medium. A dryaprotic organic solvent thus is preferred. Trace amounts of water, suchas may be present in commercially dried solvents, can be tolerated;however, it is preferred that cyclization be carried out under anhydrousconditions. Suitable solvents include, for example, aromatic compoundsincluding aromatic hydrocarbons, such as, benzene, toluene, xylene, andthe like, as well as chlorobenzene, nitrobenzene, nitromesitylene, andthe like; halogenated aliphatic hydrocarbons, such as chloroform,methylene chloride, carbon tetrachloride, 1,2-dichloroethane (ethylenechloride), 1,1,2-trichloroethane, 1,1-dibromo-2-chloroethane; and othersolvents recognized by those skilled in the art as suitable forFriedel-Crafts type reactions, including, among others, carbon disulfideand nitromethane. Preferred solvents are aromatic hydrocarbons,particularly benzene, toluene, and xylene, and, most particularly,toluene, and halogenated aliphatic hydrocarbons, particularly methylenechloride and ethylene chloride.

Any of the solvents which are employed in the preparation of thesulfinyl chloride can also be used in carrying out the cyclization ofthe azetidinone sulfinyl chloride. Thus, the sulfinyl chloride need notbe isolated from the reaction mixture in which it was generated beforecyclization can be carried out. However, when this method of cyclizationis employed, it is essential that the reaction mixture containing thesulfinyl chloride starting material be treated prior to use to removefirst, the epoxide compound and then the calcium oxide, and any reactionproducts thereof. This can conveniently be achieved by first distillingthe reaction mixture to remove the low-boiling epoxide, and thenfiltering the mixture to remove the calcium oxide as well as all otherinsolubles. The resulting filtrate then is ready for use in theFriedel-Crafts catalyzed cyclization.

Cyclization of the azetidinone sulfinyl chloride is carried out at atemperature ranging from about -20° C. to about +100° C., andpreferably, between about 10° C. and 60° C. The optimum temperature ofcyclization is determined by the particular Friedel-Crafts catalystwhich is employed. For example, when stannic chloride is employed,cyclization proceeds at room temperature, whereas, when otherFriedel-Crafts catalysts are employed, higher temperatures may berequired.

In order to ensure completion of the cyclization reaction, at least oneequivalent of the Friedel-Crafts catalyst is employed for each mole ofthe sulfinyl chloride starting material, Using less than one equivalentof the Friedel-Crafts catalyst reagent may result in a lower conversionof product and thus may leave a portion of the sulfinyl chlorideunreacted. Typically, the amount of Friedel-Crafts catalyst reagentwhich is employed will range from slightly over one equivalent to abouttwo equivalents per mole of the sulfinyl chloride. Preferably about 1.1equivalents of the catalyst reagent is employed per mole of the sulfinylchloride.

The time of the reaction generally will range from about 15 minutes toabout 2 hours, the reaction time being dependent to some extent upon theparticular reactants, the solvents employed, and the temperature atwhich the reaction is carried out. Usually, the reaction will becompleted after the reactants have been maintained in contact at thepreferred temperature for about one hour to about 16 hours. The reactionmixture can easily be monitored, for example, by comparative thin-layerchromatography, to determine when the cyclization reaction has reachedcompletion.

The 3-exomethylenecepham sulfoxides produced by cyclization of thesulfinyl chlorides of this invention can be isolated and purified byemploying conventional experimental techniques. These includechromatographic separation, filtration, crystallization,recrystallization and like methods.

The 3-exomethylenecepham sulfoxide cyclization products are useful asintermediates in the preparation of antibiotic compounds. The sulfoxidescan be reduced by known procedures, typically with phosphoroustrichloride or phosphorous tribromide in dimethylformamide, to providethe corresponding 3-exomethylenecephams.

The exomethylenecephams can be employed in the preparation of novelcephem antibiotics of the formula ##STR24## in which B is, for example,chloro, bromo or methoxy. Such chemical conversions of3-exomethylenecepham compounds have been disclosed in the chemicalliterature [Robert R. Chauvette and Pamela A. Pennington, Journal of theAmerican Chemical Society, 96, 4986 (1974)].

In general, the 3-exomethylenecepham compounds are converted by lowtemperature ozonolysis to 3-hydroxycephems which, in turn, can betreated with diazomethane at room temperature in teytrahydrofurancontaining 1 equivalent of triethylamine to afford the 3-methoxycephemderivatives. The 3-halocephems are derived from the 3-hydroxycephemesters by treatment with a halogenating reagent such as phosphoroustrichloride or phosphorous tribromide in N,N-dimethylformamide.

The corresponding cephem acids exhibit potent antibacterial activity.These are available by cleavage of the ester function. Deesterificationcan be achieved, depending on the nature of the protecting group, by anyof several recognized procedures, including (1) treatment with an acidsuch as trifluoroacetic acid, formic acid, hydrochloric acid or thelike; (2)treatment with zinc and an acid such as formic acid, aceticacid or hydrochloric acid; or (3) hydrogenation in the presence ofpalladium, platinum, rhodium or a compound thereof, in suspension, or ona carrier such as barium sulfate, carbon, alumina or the like.

This invention is further illustrated by reference to the comparativeexamples which follow. It is not intended that this invention be limitedin scope by reason of any of the examples provided herein.

EXAMPLE 1 Preparation of p-Nitrobenzyl7-Phenoxyacetamido-3-exomethylenecepham-4-carboxylate-1-oxide.

A. Reaction in the absence of calcium oxide.

Toluene (1.5 liters) was dried azeotropically with removal of 150 ml. ofmaterial. An additional 50 ml. was removed for use in the transfer ofreactants to the reaction system. Heating was discontinued, and 50 gramsof p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 23 gramsof N-chlorophthalimide were added. A Dean-Stark water trap was added tothe system, and an approximately 1:1 mixture of calcium chloride andmagnesium oxide having a total weight of 14.3 grams was added to thewater trap. Heat was reapplied, and 45 ml. of propylene oxide wereadded, the mixture refluxing at 102° C. The mixture became clear afterabout 70 minutes. After 75 minutes an nmr was run on a sample of thereaction mixture, and the presence of the sulfinyl chloride intermediatewas indicated. After 100 minutes, the water trap containing the calciumchloride and magnesium oxide mixture was replaced by a fresh water trap,and the mixture was allowed to distill. Over the next 35 minutes, 315ml. of material were removed, the temperature of the reaction mixturerising to 110.5° C. The mixture was then cooled to 10° C. over a 20minute period. The reaction mixture was filtered, and the filtrate wasadded to a precooled mixture of 25 ml. of stannic chloride in toluene.The resulting mixture was allowed to stir overnight during which time ared cake formed. The cake was filtered and then was extracted with 250ml. of acetone and 500 ml. of ethyl acetate. The resulting extract waswashed with 1 liter of water and then with 500 ml. of brine. The organicmixture was evaporated to about one-half volume and was allowed tocrystallize with cooling. The resulting mixture was filtered, and thesolid was dried in vacuo at room temperature to obtain 22.7 grams(45.4%) of the title compound.

B. Reaction in the presence of calcium oxide.

Toluene (2.0 liters) was dried azeotropically with removal of 200 ml. ofmaterial. An additional 100 ml. of toluene was removed for use intransferring reactants to the reaction system. Heating was discontinued,and 50 grams of p-nitro-benzyl6-phenoxyacetaido-2,2-dimethylpenam-3-carboxylate-1-oxide, 22 grams ofN-chlorophthalimide, and 22 grams of calcium oxide were added. Heat wasapplied, and 35 ml. of propylene oxide were added, providing a refluxtemperature of 103°-104° C. The mixture was heated for 75 minutes at104° C. and then was distilled for 30 minutes with removal of 545 ml. ofmaterial, the temperature of the reaction mixture rising to 110° C. Theresulting mixture then was cooled to 10° C. and filtered. The filtratewas added to a mixture of 50 ml. toluene and 25 ml. of stannic chlorideprecooled to 0° C. The resulting mixture then was stirred for 10 hourswith formation of a solid. The solid was collected by filtration andthen was extracted with a mixture of 500 ml. of ethyl acetate and 250ml. of acetone. The extract was washed with 500 ml. of water, evaporatedto one-half volume, and cooled overnight. The title compound (28.55 g.;57.1%) was obtained.

EXAMPLE 2

Preparation of p-Nitrobenzyl7-Phenylacetamido-3-exomethylenecepham-4-carboxylate-1-oxide.

A. Reaction in the absence of calcium oxide.

Toluene (2.1 liters) was dried by distillative removal of about 160 ml.of the solvent. An additional 50 ml. of toluene were removed for use intransferring the reactants to the reaction medium. Heating wasdiscontinued, and 17.1 grams (34 mmoles) of p-nitrobenzyl6-phenylacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, 7.8 grams(37.4 mmoles) of N-chlorophthalimide, and 12 ml. of propylene oxide wereadded. The mixture was refluxed at 103° C. for 100 minutes after whichdistillative removal was begun. A total of 170 ml. of material wasremoved over about 30 minutes. The resulting mixture was cooled to 0°-5°C. The resulting crystalline phthalimide by-product then was removed byfiltration. The filtrate was added to a precooled mixture of 8.5 ml. ofstannic chloride in toluene. The mixture was stirred overnight duringwhich time it was permitted to warm to room temperature. The resultingsolid was collected by filtration and washed thoroughly with toluene.The solid then was dissolved in a mixture of 85 ml. of acetone and 170ml. of ethyl acetate. The solution then was extracted twice with 170 ml.of water. The organic layer was separated, evaporated to about one-halfvolume, cooled to room temperature during which time crystallizationoccurred. The title compound (4.0 grams; 25%) was recovered byfiltration.

B. Reaction in the presence of calcium oxide.

The reaction of Part A was repeated with the exception that calciumoxide was included in the reaction mixture. The following amounts ofmaterials were employed: 48.5 grams (100 mmoles) of p-nitrobenzyl6-phenylacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide; 48 grams ofcalcium oxide; 22 grams of N-chlorophthalimide; and 35 ml. of propyleneoxide. The title compound (14.9 grams; 32.6%) was obtained.

EXAMPLE 3 Preparation of 2,2,2-Trichloroethyl7-Phenoxyacetamido-3-exomethylenecepham-4-carboxylate-1-oxide.

A. Reaction in the absence of calcium oxide.

Two liters of toluene were dried by distillative removal of 200 ml. ofthe material. Heating was discontinued, and 49.8 grams (100 mmoles) of2,2,2-trichloroethyl6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 20.4grams of N-chlorophthalimide were added. The mixture was heated, and 35ml. of propylene oxide were added. The total mixture was refluxed atabout 103° C. for about 100 minutes after which 705 ml. of the mixturewere removed by distillation over a 35 minute period, the temperature ofthe mixture rising from 103° C. to 110° C. The mixture was cooled to5°-10° C. and then was filtered. The filtrate was added to a pre-cooledmixture of 50 ml. of toluene and 25 ml. of stannic chloride. Theresulting mixture, blood red in color and devoid of any solid, wasstirred for 15 minutes during which time the color changed to a mudbrown and a small amount of solid appeared. The mixture was stirredovernight and then was filtered to obtain a light brown granular cake.The cake was dissolved in ethyl acetate. The ethyl acetate solution waswashed twice with water. The organic layer then was evaporated to athick gum. The gum was allowed to stand overnight at room temperatureafter which methanol was added to the gum. Crystallization occurred. Themixture was filtered and washed with methanol to obtain 14.4 grams(28.9%) of the title compound.

B. Reaction in the presence of calcium oxide.

The reaction of Part A was repeated with the exception that 25 grams ofcalcium oxide were included in the reaction mixture. The title compound(18.6 grams; 37.3%) was recovered.

EXAMPLE 4 Preparation of p-Nitrobenzyl7-Phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide (pilot plantscale in stainless steel).

A. Reaction in absence of calcium oxide.

To a thirty gallon stainless steel still were added 76 liters oftoluene. The toluene was dried by distillative removal of about 19liters of material. An additional 14 liters of toluene were removedleaving about 43 liters in the still. The toluene, under nitrogen, thenwas cooled to about 70° C., and 1.75 kg. of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide were added.Heat was added, and, when the temperature of the mixture reached about85° C., 1,400 ml. of propylene oxide were added. Heating was continued,the mixture reaching 102° C. at reflux. A total of 700 grams ofN-chlorophthalimide then was added in 87.5 gram portions atapproximately 7 minute intervals. Prior to completion of the addition ofthe N-chlorophthalimide, 350 ml. of propylene oxide were added. Another175 ml. of propylene oxide were added appproximately 1 hour aftercompletion of N-chlorophthalimide addition. The mixture was refluxed at100°-102° C. for 2.5 hours following the first addition ofN-chlorophthalimide. The mixture, having a volume of 52.5 liters, thenwas cooled to about 61° C., and concentration of the mixture was begun,the volume of the material upon completion being about 38 liters. Themixture then was filtered into a 30 gallon glass-lined still containinga mixture of 875 ml. of stannic chloride and 13 liters of toluenepre-cooled to -2° C. The temperature rose to +14 C. and was cooledto0°-5° C. The mixture then was stirred overnight. The resulting redprecipitate was filtered, and the solid was dissolved in a mixture of8.75 liters of acetone and 17.5 liters of ethyl acetate. The solutionwas washed with 17.5 liters of water and then with 17.5 liters of brine.It was separated, concentrated to 15.5 liters, cooled to 0°-5° C., andstirred overnight. The resulting mixture then was filtered, and thecollected solid was washed with 1.75 liters of ethyl acetate and driedat 45°-50° C. to obtain 389.6 grams (23.7%) of the title compound.

B. Reaction in the presence of calcium oxide.

This reaction was carried out under substantially the same conditions asthose employed in Part A with the exception that the N-chlorophthalimidewas added in one portion and the reaction was run in a 75 gallonstainless steel still and was scaled up to the following quantities ofmaterials:

144 liters of toluene (dried by binary distillation);

5.25 kg. of calcium oxide;

5.25 kg. of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide;

2,415 grams of N-chlorophthalimide;

4.2 liters of propylene oxide;

2,625 ml. of stannic chloride in 39 liters of toluene;

23.6 liters of acetone and 52.5 liters of ethyl acetate;

105 liters of water.

Employing the conditions of Part A on the above quantities there wereobtained 2.47 kg. (47.4%) of the title compound.

EXAMPLE 5 Preparation of p-Nitrobenzyl7-Phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide (pilot plantscale in glass).

A. Reaction in absence of calcium oxide.

To a 30 gallon glass-lined still were added 56 liters of toluene. Thetoluene was dried by binary distillation with removal of about 9 litersof distillate. The mixture was cooled to room temperature and was purgedwith nitrogen. Of the remaining toluene, 17.5 liters were removed toserve as solvent for the N-chlorophthalimide reactant, and an additional4.4 liters were removed to be used as transfer rinses. The remainingtoluene was heated, and, upon reaching about 85° C., 1.75 kg. ofp-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxidewere added. Upon reaching about 90° C., 1,400 ml. of propylene oxidewere added after which 700 grams of N-chlorophthalimide in 17.5 litersof toluene were added over a period of about 70 minutes. During theaddition of the N-chlorophthalimide solution, an additional 350 ml. ofpropylene oxide were added. Upon completion of the N-chlorophthalimideaddition, another of 175 ml. of propylene oxide followed by a further150 ml. of the propylene oxide were added. The resulting mixture, havinga reflux temperature of about 102°-103° C., was heated at reflux for atotal of 3 hours and 40 minutes after initial addition of theN-chlorophthalimide. The mixture then was permitted to cool. Uponreaching about 43° C., the mixture was concentrated in vacuo until thevolume had been reduced to about 42 liters. The mixture then wasfiltered, and the filtrate was added to a 30 gallon glass-lined still.To the mixture then were added 858 ml. of stannic chloride, thetemperature of the mixture rising from 14° C. to 17° C. The mixture wasstirred overnight during which time a red precipitate formed. Theprecipitate was filtered and was washed with about 4 liters of toluene.The red precipitated then was dissolved in 8.75 liters of acetone. Ethylacetate (17.5 liters) and water (17.5 liters) then were added. Theresulting mixture was stirred and then was separated. The organic layerwas washed with 1.75 liters of brine and then concentrated to about 16liters. The concentrate was cooled to 0°-5° C. and was stirredovernight. The resulting mixture was filtered, and the collected solidwas washed with 1 liter of ethyl acetate and vacuum dried at 40°-45° C.to obtain 70.16 grams (4.1%) of the title compound.

B. Reaction in the presence of calcium oxide.

To a 200 gallon glass-lined still were added 400 liters of binary-driedtoluene. To the toluene then were added 14.6 kg. of calcium oxide, 14.6kg. of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, and 6.67 kg.of N-chlorophthaimide. The mixture was heated to 100° C., and 11.68liters of propylene oxide were added over a 4 minute period. The mixturewas refluxed at a temperature of 102°-103° C. for about 90 minutes andthen was concentrated over a period of about 45 minutes. About 71 litersof material were removed, and the temperature of the mixture rose fromabout 103° C. to about 110°-111° C. The mixture then was cooled to about95° C. and was filtered into a mixture of 7.3 liters of stannic chloridein 108 liters of toluene, the total having been cooled to -6° C. Uponcompletion of the filtration, an additional 30 liters of toluene wereadded to facilitate complete transfer of the mixture. The mixture thenwas allowed to stir overnight at a temperature of from about 17°-20° C.The resulting solid was collected by filtration and was dissolved in 73liters of acetone. To the acetone solution then were added 146 liters ofethyl acetate followed by 292 liters of water. The mixture was stirredfor 5 minutes and then was separated. The organic layer was concentratedin vacuo to about 135 liters, cooled to 0°-5° C., and maintained at thattemperature overnight. The resulting mixture was filtered, and thecollected solid was washed with 25 liters of ethyl acetate and dried at50° C. to obtain 6.8 kg. (46.9%) of the title compound.

EXAMPLE 6 Preparation of p-Nitrobenzyl7-Phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide.

A. Reaction in the absence of calcium oxide.

Two liters of toluene were dried by distillative removal of 200 ml. ofthe material. Heating was discontinued, and 50 grams of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 23 gramsof N-chlorophthalimide were added. The mixture was heated, and 35 ml. of1,2-epoxybutane were added. The total mixture was refluxed at about 108°C. for about 78 minutes after which 440 ml. of the mixture were removedby distillation over a 22 minute period. The mixture was cooled to 10°C. and then was filtered. The filtrate was added to a pre-cooled mixtureof about 40 ml. of toluene and 25 ml. of stannic chloride. The resultingmixture was bright red-orange and contained a granular precipitate. Themixture was stirred for about one hour with ice-bath cooling and thenwas stirred at room temperature overnight. The mixture was filtered, andthe filter cake was dissolved in 150 ml. of methanol. The solution wasstirred for 3.5 hours and refrigerated overnight to obtain 22.8 grams(45.6%) of the title compound.

B. Reaction in the presence of calcium oxide.

The reaction of Part A was repeated with the exception of 25 grams ofcalcium oxide was included in the reaction mixture. The title compound(29.4 grams; 59.1%) was recovered.

EXAMPLE 7

Preparation of p-Nitrobenzyl7-Phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide.

A. Reaction in the absence of calcium oxide.

Two liters of toluene were dried by distillative removal of 200 ml. ofthe material. Heating was discontinued, and 50 grams of p-nitrobenzyl6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 15.2grams of N-chlorosuccinimide were added. The mixture was heated, and 35ml. of propylene oxide were added. The total mixture was refluxed atabout 104° C. for about 100 minutes after which 725 ml. of the mixturewere removed by distillation over a 35 minute period, the temperature ofthe reaction mixture rising from about 103° C. to 110.5° C. The mixturewas cooled to 10°C. and then was filtered. The filtrate was added to aprecooled mixture of 50 ml. of toluene and 25 ml. of stannic chloride.The mixture was stirred overnight and then for 10 minutes at 5°-10° C.The mixture then was filtered, and the collected solid was dissolved ina mixture of 250 ml. of acetone and 500 ml. of ethyl acetate. Thesolution was washed with 500 ml. of water and evaporated to aboutone-half volume. No crystallization occurred. The mixture was seededwith a sample of the title compound and refrigerated. However, nocrystallization was achieved even with seeding and after three days ofrefrigeration. The product yield was quite low, probably substantiallybelow 20%.

B. Reaction in the presence of calcium oxide.

The reaction of Part A was repeated with the exception that 25 grams ofcalcium oxide were included in the reaction mixture and 16.6 grams ofN-chlorosuccinimide were used. The title compound (23.35 grams; 46.7%)was recovered.

I claim:
 1. In a process for preparing a 3-exomethylenecepham sulfoxideof the formula ##STR25## by
 1. reacting a penicillin sulfoxide of theformula ##STR26## with an N-chloro halogenating agent at a temperatureof from about 75° C. to about 135° C. in an inert solvent underanhydrous conditions and in the presence of an amount of an epoxidesufficient at least to account for any hydrogen chloride which may beformed, said epoxide having the formula ##STR27## in which R_(x) ishydrogen or methyl; and in which, in the above formulae, R₁ is acarboxylic acid protecting group; and R is(a) hydrogen, C₁ -C₃ alkyl,halomethyl, cyanomethyl, benzyloxy, 4nitrobenzyloxy, t-butyloxy,2,2,2-trichloroethoxy, 4-methoxybenzyloxy,3-(2-chlorophenyl)-5methylisoxazol-4-yl; (b) the group R' in which R' isphenyl or phenyl substituted with 1 or 2 halogens, protected hydroxy,nitro, cyano, trifluoromethyl, C₁ -C₄ alkyl, or C₁ -C₄ alkoxy; (c) agroup of the formula R"-(Q)_(m) -CH₂ - in which R" is R' as definedabove, 1,4-cyclohexadienyl, 2-thienyl, or 3-thienyl; m is 0 or 1; and Qis O or S; subject to the limitation that when m is 1, R" is R'; or (d)a group of the formula ##STR28## in which R" is as defined above, and Wis protected hydroxy or protected amino; to produce a sulfinyl chlorideof the formula ##STR29## in which R and R₁ are as aforedefined; (2)treating the resulting reaction mixture to remove said epoxidetherefrom; (3) filtering insolubles from the epoxide-free mixture; and(4) treating said epoxide-free mixture with a Friedel-Crafts catalyst ata temperature of from about -20° C. to about +100° C. to produce theaforementioned 3-exomethylenecepham sulfoxide; the improvement whichcomprises carrying out step (1) in the presence of from about 100 gramsto about 500 grams of calcium oxide per mole of the penicillinsulfoxide.
 2. Process of claim 1, in which R is(a) hydrogen, C₁ -C₃alkyl, halomethyl, cyanomethy, benzyloxy, 4-nitrobenzyloxy, t-butyloxy,2,2,2-trichloroethoxy, 4-methoxybenzyloxy,3-(2-chlorophenyl)-5-methylisoxazol-4-yl; (b) the group R' in which R'is phenyl or phenyl substituted with 1 or 2 halogens, protected hydroxy,nitro, cyano, trifluoromethyl, C₁ -C₄ alkyl, or C₁ -C₄ alkoxy; or (c) agroup of the formula R"--(Q)_(m) --CH₂ -- in which R" is R' as definedabove, 1,4-cyclohexadienyl, 2-thienyl, or 3-thienyl; m is 0 or 1; and Qis O or S; subject to the limitation that when m is 1, R" is R'. 3.Process of claim 2, in which R is a group of the formula R"--(Q)_(m)--CH₂ --.
 4. Process of claim 3, in which R" is R'.
 5. Process of claim4, in which R' is phenyl.
 6. Process of claim 5, in which m is 0 . 7.Process of claim 5, in which m is
 1. 8. Process of claim 7, is which Qis oxygen.
 9. Process of claim 3, in which R" is 2-thienyl and m iszero.
 10. Process of claim 1, in which R₁ is C₄ -C₆ tert-alkyl,2,2,2-trihaloethyl, 2-iodoethyl, benzyl, p-nitrobenzyl,succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, benzhydryl, C₂-C₆ alkanoyloxymethyl, dimethylallyl, phenacyl, or p-halophenacyl. 11.Process of claim 10, in which R₁ is t-butyl, benzyl, p-nitrobenzyl,p-methoxybenzyl, benzhydryl, or 2,2,2-trichloroethyl.
 12. Process ofclaim 1, in which the reaction of step (1) is carried out in thepresence of from about 2 to about 10 moles of the epoxide compound permole of the penicillin sulfoxide.
 13. Process of claim 12, in which theepoxide compound is 1,2-epoxybutane.
 14. Process of claim 12, in whichthe epoxide compound is propylene oxide.
 15. Process of claim 1, inwhich the reaction is carried out in the presence of toluene as solvent.16. Process of claim 1, in which the N-chloro halogenating agent is acompound of the formula ##STR30## in which R₄ is hydrogen, chloro, C₁-C₃ alkyl, cyclohexyl, phenyl, or phenyl substituted with chloro, bromo,methyl, or nitro, and R₅ is R₆ --X-- in which R₆ is C₁ -C₃ alkyl,cyclohexyl, phenyl, or phenyl substituted with chloro, bromo, methyl, ornitro, and X is ##STR31## or R₄ and R₅ taken together with the nitrogento which they are bonded define a heterocyclic structure of the formula##STR32## in which Y is o-phenylene or --(CH₂)_(n) -- in which n is 2 or3; or a structure of the formula ##STR33## in which Y is as hereinbeforedefined.
 17. Process of claim 16, in which the N-chloro halogenatingagent has the formula ##STR34## in which Y is o-phenylene or --CH₂ --CH₂--.
 18. Process of claim 17, in which the N-chloro halogenating agent isN-chlorosuccinimide.
 19. Process of claim 17, in which the N-chlorohalogenating agent is N-chlorophthalimide.